Electrochemical evidence of nitrate release from the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid and its antinociceptive and anti-inflammatory activities in mice.

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.

Sex Differences in Interleukin-6 Responses Over Time Following Laboratory Pain Testing Among Patients With Knee Osteoarthritis.

Epidemiological studies suggest that women are not only at a higher risk for developing knee osteoarthritis (KOA), but also report greater symptom severity compared to men. One potential underlying mechanism of these sex differences may be exaggerated inflammatory responses to pain among women compared to men. The present study examined sex differences in interleukin-6 (IL-6) response over time following experimental pain testing. We hypothesized that women, when compared to men, would show greater IL-6 reactivity when exposed to acute pain in a human laboratory setting. Eighty-four participants (36 men and 48 women) with KOA scheduled for total knee arthroplasty underwent a quantitative sensory testing (QST) battery. A total of seven IL-6 measurements were taken, twice at baseline, once immediately after QST, and every 30 minutes up to 2 hours after QST. Consistent with our hypothesis, women, when compared to men, showed accelerated increases in IL-6 levels following laboratory-evoked pain, even after controlling for body mass index, marital status, clinical pain, evoked pain sensitivity, and situational pain catastrophizing. Given that KOA is a chronic condition, and individuals with KOA frequently experience pain, these sex differences in IL-6 reactivity may contribute to the maintenance and/or exacerbation of KOA symptoms. PERSPECTIVES: The present study demonstrates that women, when compared to men, exhibit greater IL-6 reactivity after exposure to laboratory-evoked pain. Such sex differences may explain the mechanisms underlying women's higher chronic pain risk and pain perception, as well as provide further insight in developing personalized pain interventions.

The critical role of amygdala subnuclei in nociceptive and depressive-like behaviors in peripheral neuropathy.

The amygdala is an important component of the limbic system that participates in the control of the pain response and modulates the affective-motivational aspect of pain. Neuropathic pain is a serious public health problem and has a strong affective-motivational component that makes it difficult to treat. The central (CeA), basolateral (BLA) and lateral (LA) nuclei of the amygdala are involved in the processing and regulation of chronic pain. However, the roles of these nuclei in the maintenance of neuropathic pain, anxiety and depression remain unclear. Thus, the main objective of this study was to investigate the role of amygdala subnuclei in the modulation of neuropathic pain, including the affective-motivational axis, in an experimental model of peripheral neuropathy. The specific goals were as follows: (1) To evaluate the nociceptive responses and the patterns of activation of the CeA, BLA and LA in neuropathic rats; and (2) To evaluate the effect of inactivating the amygdala nuclei on the nociceptive response, anxiety and depressive behaviors, motor activity, and plasma stress hormones in animals with neuropathic pain. Thus, mechanical hyperalgesia and allodynia, and the pattern of c-Fos staining in the amygdala subnuclei were evaluated in rats with chronic constriction of the sciatic nerve, as well as sham-operated and naïve rats. Once the amygdala subnuclei involved in neuropathic pain response were defined, those subnuclei were pharmacological inactivated. The effect of muscimol inactivation on the nociceptive response (hyperalgesia and allodynia), anxiety (elevated plus-maze), depressive-like behavior (forced swim test), motor activity (open field), and plasma stress hormone levels (corticosterone and adrenocorticotropic hormone) were evaluated in sham-operated and neuropathic animals. The results showed that the anterior and posterior portions of the BLA and the central portion of the CeA are involved in controlling neuropathic pain. The inactivation of these nuclei reversed hyperalgesia, allodynia and depressive-like behavior in animals with peripheral neuropathy. Taken together, our findings improve our understanding of the neurocircuitry involved in persistent pain and the roles of specific amygdala subnuclei in the modulation of neuropathic pain, including the neurocircuitry that processes the affective-motivational component of pain.

Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine.

Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.

High Plasma Pentraxin 3 Levels in Diabetic Polyneuropathy Patients with Nociceptive Pain.

Diabetic polyneuropathy is the most common neurologic complication of diabetes mellitus. Underlying mechanisms of diabetic polyneuropathy are related to various metabolic and inflammatory pathways. Pentraxin 3 (PTX3) is an acute phase protein that is produced locally at the inflammatory sites by several cell types. Thioredoxin binding protein 2 (TBP2) is a thioredoxin regulator involved in intracellular energy pathways and cell growth. We measured the plasma levels of PTX3 and TBP2 in type 2 diabetic patients (n = 27) with pain complaints and compared their levels with those of healthy age- and sex-matched subjects (n = 24). Moreover, the diabetic patients were divided into two groups using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale: patients with nociceptive pain that is caused by tissue damage and patients with neuropathic pain that is caused by nerve damage. Patients with LANSS scores of < 12 were considered to have nocicceptive pain (n = 15), while patients with LANSS scores of ≥ 12 were considered to have neuropathic pain (n = 12). We found that PTX3 levels were significantly higher in diabetic patients compared to controls (p = 0.03), but there was no significant difference in the TBP2 levels. Importantly, patients with nociceptive pain had significantly higher PTX3 levels compared to patients with neuropathic pain (p < 0.05). Thus, plasma PTX3 levels can be helpful for discrimination of nociceptive pain from neuropathic pain in diabetic patients. We propose that PTX3 may contribute to the onset of nociceptive pain.

[An antinociceptive effect of chondroprotectors: a myth or a reality?].

Authors reviewed the literature on the efficacy of chondroprotectors in the treatment of chronic pain syndromes in comparison with placebo and other analgesics to discover the own antinociceptive effect of these drugs and mechanisms by which it occurs. Authors evaluated the results of various clinical studies on the effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOA) on chronic pain syndrome in osteoarthritis and low back pain. We compared their effects with those of NSAIDs, celecoxib, or placebo. Assessment of pain and functional status was performed using WOMAC, VASandLeken's index as well as the Roland--Morrisquality of life questionnaire. The review of a number of clinical studies revealed a definite antinociceptive and anti-inflammatory effect of SYSADOA comparable with NSAIDs not only in the treatment of osteoarthritis, but also in chronic back pain, which is characterized by early onset and gradual development with a long-term retention of the result even after discontinuation of therapy. It has been shown that SYSADOA are able to reduce the level of inflammatory cytokines in the blood (IL-6, C-reactive protein) and to activate the production of anti-inflammatory cytokine IL-10 in the synovial membrane. It is shown that blocking of the effects of interleukin 1-beta and thereby inhibition of inflammatory enzymes like nitric oxide synthase and cyclooxygenase-2 is one of the points of glucosamine chondrocytes application. The data obtained in numerous studies that confirm the ability of SYSADOA to inhibit proinflammatory cytokines open the new perspectives for their use in the treatment of not only joint pain but also other chronic pain syndromes.

Bis(phenylimidazoselenazolyl) diselenide: a compound with antinociceptive properties in mice.

The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25-100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25-100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10-50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10-50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.

Analgesia and serum assays of controlled-release dihydrocodeine and metabolites in cancer patients with pain.

Aim of the study was to assess dihydrocodeine (DHC) and metabolites concentrations and their correlations with DHC analgesia in cancer patients with pain. Thirty opioid-naive patients with nociceptive pain intensity assessed by VAS (visual analogue scale) > 40 received controlled-release DHC as the first (15 patients, 7 days) or as the second opioid (15 patients, 7 days). Blood samples were taken on day 2, 4 and 7 at each study period. DHC and its metabolites were assayed by HPLC. DHC provided satisfactory analgesia when administered as the first or the second opioid superior to that of tramadol. When DHC was the first opioid administered, DHC and dihydrocodeine-6-glucuronide (DHC-6-G) concentrations increased in the second and the third comparing to the first assay. A trend of nordihydromorphine (NDHM) level fall between the first and the third assay was noted; trends of dihydromorphine (DHM) level increase in the second relative to the first determination and decrease in the third compared to the second assay were observed. When DHC followed tramadol treatment a trend of DHC concentration increase in the second relative to the first assay was noted. DHC-6-G level increased in the second and in the third comparing to the first determination; NDHM and DHM concentrations were stable. DHC and DHC-6-G concentrations increased similarly during both treatment periods which suggest their prominent role in DHC analgesia. Few significant correlations were found between DHC dose, DHC and metabolites serum concentrations with analgesia suggesting the individual DHC dose titration.

Central corticotropin-releasing factor (CRF) may attenuate somatic pain sensitivity through involvement of glucocorticoids.

Corticotropin-releasing factor (CRF) is an important regulator of physiological functions and behavior in stress. Analgesia is one of the characteristics of stress reaction and CRF is involved in providing stress-induced analgesia, however, the underlying mechanisms remain to be determined. Exogenous CRF mimics stress effects on pain sensitivity and causes analgesic effect. The present study was performed to investigate the participation of endogenous glucocorticoids in analgesic effects induced by central administration of CRF in anesthetized rats. The participation of glucocorticoids was studied by pharmacological suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis as well as an occupation of glucocorticoid receptors by its antagonist RU 38486. Since CRF administration causes the release of ß-endorphin from the pituitary, the opioid antagonist naltrexone was used to determine the contribution of opioid-dependent mechanism to CRF-induced analgesia. An electrical current threshold test was applied for measurement of somatic pain sensitivity in anesthetized rats. Intracerebroventricular administration of CRF (2 µg/rat) caused analgesic effects (an increase of pain thresholds) and an increase in plasma corticosterone levels. Pretreatment with naltrexone did not change analgesic effects of central CRF as well as corticosterone levels in blood plasma. However, pharmacological suppression of the HPA axis leading to an inability of corticosterone release in response to CRF resulted in an elimination of CRF-induced analgesic effects. Pretreatment with RU 38486 also resulted in an elimination of CRF-induced effects. The data suggest that CRF-induced analgesic effects may be mediated by nonopioid mechanism associated with endogenous glucocorticoids released in response to central CRF administration.